基底外侧杏仁核抑制性神经环路的构建及其在恐惧中的作用和机制

基底外侧杏仁核(BLA)是参与恐惧记忆和恐惧消退的关键核团。BLA抑制性神经环路在恐惧信息处理过程中扮演重要角色。BLA广泛接受中枢不同脑区的多种神经纤维投射，然而目前并不清楚不同的神经投射是如何调节不同的抑制性神经环路进而参与恐惧信息处理；对恐惧记忆消退训练是形成新的抑制性记忆还是记忆擦除仍存在广泛争论。因此，本研究综合应用逆向跨单突触病毒追踪、荧光显微光学切片断层成像技术、光学遗传学、离体与在体电生理等多种先进技术，将完整构建BLA主要抑制性神经元的全脑连接图谱，系统研究BLA的抑制性神经环路在恐惧记忆和消退中的作用、弥散性调制系统参与的抑制环路功能以及神经调节素NRG1-ErbB4信号对这些功能的调控及其分子机制；同时，选取环境、线索依赖的恐惧条件反射作为实验模型，从分子细胞到神经环路水平全面研究记忆消退和擦除的发生机制，以及应激影响记忆消退的机制，该研究不仅有助于人们对杏仁核不同抑制性神经环路的结构和功能、对恐惧发生机制有更深入的了解，更为人们进一步理解与BLA抑制性神经环路结构和功能异常相关疾病如创伤后应激障碍和焦虑症等的发病机理提供新的思路。

Basolateral amygdale (BLA) is critical for fear memory. Recent studies show that inhibitory neurons in BLA are essential for fear encoding and retrieval. BLA receives extensive inputs from multiple regions of the brain; however, it is currently largely unknown how different inputs involve in fear processing through the regulation of distinct subgroups of inhibitory neurons in BLA. Up to now, there are still many debates about whether extinction is fear erasure or inhibition. Thus, with a combination of monosynaptic retrograde trans-synaptic tracing based on modified rabies virus, fluorescence micro-optical sectioning tomography, in vitro and in vivo electrophysiology, optogenetics, and animal behavior tests, we will perform whole-brain mapping of direct inputs onto inhibitory neurons of BLA, followed by a systematic study of their roles in fear memory and extinction and their regulation by NRG1-ErbB4 signaling. By using contextual and cue dependent fear conditioning paradigm, we will also study the molecular, cellular and neural circuitry mechanisms underlying memory extinction and erasure, and how stress regulates memory extinction. Our study will add to our knowledge of the structure and function of inhibitory circuits in BLA and the mechanism(s) underlying fear behavior, and further improve our understanding of the pathophysiology of diseases associated with dysfunctions of BLA inhibitory circuitry such as PTSD and anxiety.